Human papillomavirus vaccination in the European Union/European Economic Area and globally: a moral dilemma

While many European Union/European Economic Area (EU/EEA) countries recently expanded human papillomavirus (HPV) vaccination to boys, HPV vaccine supply is currently limited for girls in low- and middle-income countries (LMIC) that are severely affected by HPV. Globally, about 50% of countries have introduced HPV vaccination. Some LMIC with high burden of cervical cancer have not yet introduced HPV vaccination, or are reaching suboptimal vaccination coverage. While WHO issued a call for cervical cancer elimination in 2018, a global shortage of HPV vaccines is currently predicted to last at least until 2024. We reviewed national policies of EU/EEA countries and recommendations of the World Health Organization (WHO) Strategic Advisory Group of Experts on immunisation to discuss current challenges and dose-sparing options. Several EU/EEA countries have extended HPV vaccination to boys and the European Cancer Organisation has issued a resolution for elimination of all HPV-associated cancers in both sexes. The European Centre for Disease Prevention and Control concluded in its 2020 guidance that cost-effectiveness of extending routine vaccination to boys depends on several context-specific factors. The extension of HPV vaccination to boys in EU/EEA countries may affect global availability of vaccines. Temporary dose-sparing options could be considered during the COVID-19 post-pandemic period.

While many European Union/European Economic Area (EU/EEA) countries recently expanded human papillomavirus (HPV) vaccination to boys, HPV vaccine supply is currently limited for girls in low-and middle-income countries (LMIC) that are severely affected by HPV. Globally, about 50% of countries have introduced HPV vaccination. Some LMIC with high burden of cervical cancer have not yet introduced HPV vaccination, or are reaching suboptimal vaccination coverage. While WHO issued a call for cervical cancer elimination in 2018, a global shortage of HPV vaccines is currently predicted to last at least until 2024. We reviewed national policies of EU/EEA countries and recommendations of the World Health Organization (WHO) Strategic Advisory Group of Experts on immunisation to discuss current challenges and dose-sparing options. Several EU/ EEA countries have extended HPV vaccination to boys and the European Cancer Organisation has issued a resolution for elimination of all HPV-associated cancers in both sexes. The European Centre for Disease Prevention and Control concluded in its 2020 guidance that cost-effectiveness of extending routine vaccination to boys depends on several context-specific factors. The extension of HPV vaccination to boys in EU/EEA countries may affect global availability of vaccines. Temporary dose-sparing options could be considered during the COVID-19 post-pandemic period.

Background
Human papillomavirus (HPV) infection is the most frequent sexually transmitted disease and the second most common cause of cancer attributable to an infectious agent globally [1]. Cervical cancer is by far the most common malignancy causally associated with HPV infection. However, other less prevalent anogenital cancers, some emerging HPV-associated oropharyngeal cancers, and non-malignant but common anogenital warts are also causally associated with HPV infection and can affect both sexes [1]. Early diagnosis of HPV-associated precancerous lesions may lead to successful treatment before the development of HPV-associated cancer, yet organised screening is currently implemented and effective only against cervical cancer in women [2]. Since 2006, vaccines have been available to prevent HPV infection and HPV-associated illness. Three products are currently licensed in the European Union (EU): (i) the bivalent vaccine, Cervarix (GlaxoSmithKline Biologicals, Rixensart, Belgium); (ii) the 4-valent recombinant vaccine, Gardasil (MSD VACCINS, Lyon, France) and; (iii) the 9-valent vaccine, Gardasil 9 (MSD VACCINS).
In view of the large burden of cervical cancer attributable to HPV, immunisation strategies against HPV infection have initially focused exclusively on girls.
From the growing body of evidence, including clinical trials, field trials, large cohort studies and ecological studies on the impact of HPV vaccination, HPV vaccines have proven to be generally safe and effective against persistent HPV infection, anogenital warts, and pre-cancerous lesions, in particular when administered to HPV naive subjects. There is also evidence of substantial indirect (herd) protection when vaccine coverage is above 50% [3,4].
We review and discuss the implications of the expansion of HPV vaccination to boys in the European Union/ European Economic Area (EU/EEA) in light of the current cervical cancer elimination goals and of the global shortage of HPV vaccines, which is mainly affecting girls in low-and middle-income countries (LMIC).

Elimination goals and resolutions
Globally, by 2020, about half of all countries have introduced HPV vaccination, covering about one third of the eligible population of girls. Low-and middle-income countries have the lowest rates of introduction of HPV vaccination and some are struggling with its introduction while experiencing a high burden of cervical cancer and HPV-associated illness [5]. A recent update of the International Agency for Research on Cancer's GLOBOCAN data showed that 84% of cervical cancer cases still occur in low-resource settings [6].
A call for elimination of cervical cancer was issued by the World Health Organization (WHO) in May 2018, followed by the American Cancer Society in June 2018 [7,8]. In September 2019, the European Cancer Organisation passed a resolution for the elimination of all HPV-associated cancers, thus setting the bar even higher [9]. Moreover, the European Commission launched Europe's Beating Cancer Plan at the end of 2020 [10].
The WHO considers vaccination fundamental for equity in healthcare and beyond. It is one of the key elements of primary healthcare and universal healthcare coverage. The proposed Immunisation Agenda 2030 aims to "extend the benefits of vaccines to everyone, everywhere" and identifies vaccination 'coverage and equity' as one of its seven strategic priorities [11]. All vaccinations should thus be offered in an equitable way to all those that could benefit from the vaccines.

Summary of evidence for extending routine human papillomavirus vaccination to boys in EU/EEA countries
In 2008, the European Centre for Disease Prevention and Control (ECDC) produced its first guidance on HPV vaccination in EU/EEA countries following the introduction of the first two vaccines against human papillomavirus [12]. The guidance was updated in 2012 following the collection of evidence of efficacy of HPV vaccination in males [13]. In 2020, ECDC published its first evidence-based guidance on HPV vaccination, applying the methodological guidelines of the grading of recommendations, assessment, development and evaluation (GRADE) to complement and update the information included in the previous two guidance documents [14]. This document focused on four separate topics: (i) the efficacy of the 9-valent HPV vaccine licensed by the European Medicines Agency in 2015 for males and females; (ii) the efficacy and effectiveness of any licensed HPV vaccine for males; (iii) the cost-effectiveness of extending routine HPV vaccination to males and; (iv) the efficacy and effectiveness of any licensed HPV vaccine for people living with HIV. The guidance concluded that HPV vaccination is effective in males against persistent HPV infections, anal pre-cancerous lesions and anogenital warts based on direct evidence from a pivotal 4-valent recombinant HPV vaccine trial (Table 1) and on data from immuno-bridging studies for the other licensed vaccines [14].
As part of the guidance, a systematic review of studies looking at cost-effectiveness of extending routine HPV vaccination to boys was performed (Supplementary Table) and concluded that cost-effectiveness of extending HPV vaccination to boys depended on several factors, many of which are context-specific. The cost of the HPV vaccine was the main driver of the incremental cost-effectiveness ratio (ICER) when comparing a scenario of universal vaccination with a baseline scenario of vaccination of girls only. Notably, the extension of HPV vaccination to boys appeared more cost-effective compared with increasing vaccine uptake among girls in cases where vaccination coverage among girls is persistently lower than 75-80% [15]. However, this may also depend on other factors such as public health priorities (e.g. prevention of cervical cancer) and cost of the vaccine [14]. Other factors were also able to affect the ICER, including: (i) the cost-effectiveness threshold and discount rate chosen; (ii) the selected perspective; (iii) the assumed vaccination coverage reached and maintained over time in the competing scenarios; (iv) the assumed duration of protection from the immunisation; (v) the number of HPV-associated outcomes included in the model and; (vi) the prevalence of circulating HPV serotypes and of HPV-associated illness.

Policies on human papillomavirus vaccination in EU/EEA countries
As at December 2021, all EU/EEA countries have introduced HPV vaccination in their national programmes [16], and many countries have recently moved, or are planning to move, from a girls-only HPV vaccination strategy to a universal, or gender-neutral HPV vaccination strategy (Figure, Table 2), similar to what happened with vaccination against rubella that was initially only offered to girls and then extended to both sexes in combination with vaccination against mumps and measles [17].
There are several reasons that justify this decision. First, the indirect protection from vaccination of girls with suboptimal uptake, as observed in many EU/EEA countries, is in fact not sufficient to adequately protect males. Second, vaccinating only girls is not an equitable measure and does not protect men who have sex with men. Additionally, it is a less resilient strategy against sudden drops in vaccine uptake compared with a gender-neutral vaccination strategy. Finally, universal HPV vaccination is likely to be more effective and efficient in reducing HPV virus circulation in the general population even at lower levels of vaccine uptake. As at 2021, several EU/EEA countries (i.e. Austria, Belgium, Croatia, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Liechtenstein, the Netherlands, Norway, Portugal, Slovakia, Slovenia, Spain and Sweden) and the United Kingdom (UK) have extended, or have decided to extend in the coming years, HPV vaccination to boys, while other countries are discussing the opportunity to extend it soon (Figure, Table 2).

Human papillomavirus vaccine shortage
The WHO has highlighted that the current global HPV vaccination shortage, foreseen to last at least until 2024, might delay the introduction of HPV vaccination in the countries most in need [5]. In particular, there will not be enough vaccine doses available for girls from a number of LMIC with a high burden of cervical cancer. Extending HPV vaccination to boys implies a substantial increase in the number of doses to be procured and administered. At a time when coronavirus disease (COVID-19) vaccination may absorb large proportions of the resources available, extending HPV vaccination to boys may become complex because of logistical and acceptance challenges. Some of the potential barriers for HPV vaccination uptake in boys are parental knowledge, risk perception of HPV in men and limited recommendations from healthcare providers [18]. In 2019, there were ca 2,800,000 boys in each age cohort (aged 11-14 years) across the EU/EEA. If all EU/EEA countries expanded HPV vaccination to boys, each cohort of boys immunised would require about 2.8 million or 1.1 million extra doses of HPV vaccine at uptakes of 50% or 20%, respectively [19]. The choice of many EU/EEA countries to extend HPV vaccination to boys may thus further impact the limited supply of HPV vaccines at the global level. Moreover, it poses a moral dilemma between providing equitable access to HPV vaccines for all girls and boys within countries with well-established HPV vaccination programmes and providing equitable access to HPV vaccines for all girls globally [20].
Between 84% and 90% of all cervical cancers occur in LMIC and implementation of mass screening remains a major challenge in several of these countries. Recent projections showed that an estimated 11 million women from LMIC will be diagnosed with cervical cancer in the next 10-20 years. Many of these cervical cancers are diagnosed late and thus have poor prognosis [21]. In these countries, the prevention of persistent HPV infection through vaccination of all eligible girls could save millions of lives. In 2016, GAVI, the Vaccine Alliance, aimed to protect 40 million girls from cervical cancer, averting 900,000 deaths, through HPV vaccination by 2020. The objective was then re-adjusted to vaccination of 14 million girls and prevention of 300,000 deaths in light of the global shortage of HPV vaccines [22]. For the same reason, the recent introduction of HPV vaccination in some of the countries with the highest burden of HPV-associated illness and mortality in the world had to focus on a single cohort of girls instead of on multiple age cohorts as initially planned. Cervical cancer deaths are currently expected to reach 416,000 by 2035 without improvements in HPV prevention among girls globally [22]. Independent transmission-dynamic models have shown that high vaccination coverage of girls (> 90%) would lead to cervical cancer elimination in most LMIC by the end of this century [23].
Additionally, it should be noted that the average individual health benefit obtained from a dose of vaccine administered to a boy in the EU/EEA is substantially lower than the average individual health benefit obtained from a dose of HPV vaccine given to a girl in LMIC where cervical cancer screening is not implemented or well-established. The WHO's Strategic Advisory Group of Experts (SAGE) on immunisation recently recommended a temporary pause in the implementation of HPV vaccination of boys in those countries that are considering doing so [24]. It was also recommended that the vaccination of girls and boys older than 15 years (i.e. catch-up vaccination strategies) and multi-age cohort vaccination strategies should temporarily pause. Meanwhile, dose-sparing options are being investigated.

Dose-sparing options
In light of the limited evidence available, the use of a single dose of an HPV vaccine is currently not recommended. However, a substantial amount of research is ongoing. Non-randomised data from post-hoc analyses of two randomised controlled trials (RCTs) from Costa Rica and India (the latter now converted into a cohort study), using bivalent and 4-valent recombinant HPV vaccines respectively, showed that immunogenicity was still observed years after a single dose of HPV vaccination, although inferior to that observed after two or three doses [25,26]. Recent population-based data from post-licensure linkage studies from Australia, Denmark and United States (US) showed that one dose of 4-valent recombinant HPV vaccine seemed to be as effective as two or three doses to protect against highgrade cervical lesions. However, these post-licensure analyses may be subject to bias [27][28][29]. Five RCTs, two in Costa Rica, one in Kenya, one in Tanzania, one in the Gambia, and two observational studies in South Africa and Thailand, are currently investigating whether a single dose of HPV vaccine provides enough protection against HPV infection and HPV-associated illness. While more data from these studies are expected in the coming years, preliminary results seem promising [30].
Alternative dose-sparing options are also being considered. Vaccination schedules could be modified in order to spare doses and gain time during the current vaccine shortage. Different options were proposed at the SAGE meeting in October 2019, however, it was concluded that the feasibility of the suggested alternative schedules would need to be carefully assessed in each different context [24]. One cost-effective option proposed was to extend the interval between the first and the second dose of HPV vaccination, offering the first dose at the age of 9-10 years and the second dose at the age of 13-14 years. The success of this off-label vaccination schedule may be affected by the risk of dropouts after the first dose and the subsequent reduced uptake of the second dose. The age of initiation of sexual activity is also important to consider since HPV vaccination has shown the highest immunogenicity and efficacy in adolescents prior to the beginning of sexual life. The extension in time of the HPV vaccination schedule may lead to gaining some years before fully vaccinating the new cohorts with a second dose [24]. In the meantime, evidence of efficacy of a single HPV dose schedule would become available and global supply could be re-established so that global demand of HPV vaccines could be met.
Other gradual approaches may also be contemplated. The Immunisation Committee from the Province of Quebec in Canada recently recommended an off-label mixed schedule using the 9-valent HPV vaccine as a first dose, and the bivalent HPV vaccine as a second dose, until evidence of effectiveness of a single dose  During the first 2 years of the programme, HPV vaccination was administered to girls aged 13-15 years while currently it is administered to girls aged 11-12 years. Boys have been offered HPV vaccination since 2020. Females older than 12 years can obtain the HPV vaccine against prescription using out-of-pocket payment.  of HPV vaccine becomes available [31,32]. The rationale was based on immunological criteria with the objective of maximising the protection against HPV types 16 and 18, the two high-risk serotypes responsible for over 70% of HPV-associated cancers, while giving enough immunity against the seven additional types included in the 9-valent HPV vaccine responsible for additional HPV-associated cancers and anogenital warts. The mixed schedule was also considered the most cost-effective option to efficiently provide universal HPV vaccination. Careful and accurate monitoring of HPV-associated infections and illnesses (e.g. anogenital warts) was recommended in order to confirm the soundness and continuation of this off-label vaccination strategy [31].
The COVID-19 pandemic has affected national routine immunisations and may influence the future priorities of vaccination programmes in many countries. A modelling study estimated that, because of the impact of the pandemic on HPV vaccine uptake, over 130,000 cases of genital warts and between 2,882 and 6,487 In 2008, the Romanian Ministry of Health rolled out a school-based immunisation campaign providing free HPV vaccination for girls aged 10-11 years. Coverage statistics revealed that only 2.6% of the girls received vaccination and the programme was suspended. In 2009 an information campaign was launched, followed by a second vaccination programme, targeting girls aged 12-14 years. A catch-up programme was also launched, where adult women were given the opportunity to get the vaccine free of charge through their health provider. Despite the accessibility of the vaccine, uptake remained low and the school-based programme was discontinued at the end of 2011.

Table 2c
Overview of human papillomavirus vaccination policies in EU/EEA countries and the United Kingdom, 2007-2021a cases of cervical cancer will not be avoided in the US over the next 100 years, with over 60% of them occurring in the next 50 years [33].

Conclusions
Too many girls living in LMIC with a high burden of cervical cancer are not vaccinated against HPV, hence the global call for action for cervical cancer elimination. In high-income countries, including several EU/EEA countries, the priority has shifted towards the prevention of all HPV-associated illness and the equity of access to HPV vaccination for all genders thanks to successful vaccination and screening strategies against cervical cancer. In view of the current global HPV vaccines shortage which could be affected by the current COVID-19 pandemic in different ways, and given the growing global demand for HPV vaccines, there are different aspects to consider including equity of benefit, equity of access globally, current and future vaccine supply, national and international health needs and priorities, costs and political imperatives. The SAGE issued clear and sensible temporary recommendations, however, countries that have already extended HPV vaccination to boys, or have already decided to extend it, may face important challenges to provisionally reverting or modifying their decision after long debates on the opportunity to do so.
The dose-sparing options suggested by SAGE represent possible temporary solutions, in particular the extension of the time interval between the first and the second dose of the HPV vaccine. However, the communication and implementation of such temporary decisions may be difficult and might affect HPV vaccination confidence and uptake of the full two-dose schedule. The potential impact of the COVID-19 pandemic on supply and uptake of other vaccines suggests postponing any further change of the current vaccination schedules to the post-pandemic phase.